Cytokines represent a large number of secreted proteins that regulate cell growth and differentiation. These factors are especially important in regulating immune and inflammatory responses, and in regulating lymphoid development and differentiation. Not surprisingly, cytokines are critical in the pathogenesis of autoimmune diseases such as rheumatoid arthritis, SLE, IBD and psoriasis. Conversely, mutations that affect cytokines and cytokine signal pathways underlie a variety of primary immunodeficiencies. We discovered human Jak3, a kinase essential for signaling by cytokines that bind the common gamma chain, gc (IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21). We found that a mutation of Jak3 results in the primary immunodeficiency disorder SCID. After activation of receptor-associated Jaks, the next step in signal transduction is the activation of latent, cytosolic transcription factors that can also bind activated cytokine receptors, known as STATs. Work by us and other NIH scientists have revealed that mutations of STAT3 underlie the autosomal dominant form of hyperimmunoglobulin E syndrome (HIES). This work led us to understand the impact of STATs on transcriptomic regulation and epigenomic organization of lymphocytes. We found that STATs have a major impact on enhancers and superenhancers. In our previous work, we have identified BACH2 as a critical transcription for T and B cell homeostasis. We also discovered that BACH2 locus also has a very striking super-enhancer architecture. Single-nucleotide variants in the BACH2 locus are associated with several autoimmune diseases, but this year we described a new syndrome we termed BACH2-related immunodeficiency and autoimmunity (BRIDA) that results from BACH2 haploinsufficiency. We found that affected subjects had lymphocyte-maturation defects that caused immunoglobulin deficiency and intestinal inflammation. The mutations disrupted protein stability by interfering with homodimerization or by causing aggregation. We observed analogous lymphocyte defects in Bach2-heterozygous mice. More broadly, we observed that genes that cause monogenic haploinsufficient diseases are generally enriched for transcription factor genes with SE architecture. We propose that our findings may reveal a previously unrecognized implication for the presence of supe-renhancer architecture in Mendelian diseases: heterozygous mutations in genes that exhibit superenhancer structure identified by whole-exome/genome sequencing may have greater significance than previously recognized.